Optically pure dihydropyrimidine compounds and their uses for the preparation of a medicament for treatment and prevention of viral diseases
a technology of dihydropyrimidine and compound, which is applied in the field of optically pure dihydropyrimidine compound, can solve the problems of imposing a heavy economic burden on family and society, serious affecting human health,
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example 1
Preparation of (R,R)—N-(1-phenylethyl)-4-(2-chloro-4-fluorophenyl)-6-methyl-2-(2-thiazolyl)-1,4-dihydropyrimidin-5-carboxamide
[0141]
[0142]Step 1 6.06 g (50 mmol) (R)-α-methylbenzylamine and 7.11 g (50 mmol) diketene acetone adduct were placed in a 250 ml single-necked round flask, and then 100 ml N,N-dimethylformamide and 6.01 g (60 mmol) triethylamine were added, to carry out the reaction at 80-100° C. for 2 hr. After stopping the reaction, 200 ml water was added, and then the reaction mixture was neutralized with 4N hydrochloric acid to be neutral, and extracted with ethyl acetate. The obtained organic phase was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 9.33 g compound 1 (yield 91%).
[0143]Step 2 4.5 g (22.05 mmol) compound 1, 3.5 g (22.05 mmol) 2-chloro-4-fluorobenzaldehyde, 4.5 g (22.05 mmol) 2-thiazol formamidine acetate and 1.0 g (22.05 mmol) anhydrous sodium acetate were added to 100 m...
example 2
[0144]Preparation of (R)-4-(2-chloro-4-fluorophenyl)-6-methyl-2-(2-thiazolyl)-1, 4-dihydropyrimidin-5-ethylcarboxylate
[0145]
[0146]0.91 g (2 mmol) compound 2 was dissolved in 20 ml anhydrous N,N-dimethylformamide, 0.3 g (3 mmol) triethylamine was added, and 0.16 ml (2.4 mmol) acetyl chloride was added dropwise, to carry out the reaction at room temperature for 6 hr. 20 ml water was added to the reaction mixture, and then the reaction mixture was extracted with 15 ml×6 ethyl acetate. The obtained organic phase was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and separated by a flash column chromatography to obtain 0.746 g of compound 3 (yield 75%) with 1H-NMR (400 MHz, DMSO-d6) δ 1.23-1.41 (3H, m); 1.98 (3H, s); 2.17 (3H, s); 4.96-5.0 (1H, m); 6.59 (1H, s); 7.07-7.42 (8H, m); 7.98-7.99 (1H, d) 8.02-8.03 (1H, d) 8.63-8.64 (1H, d); MS (EI) 496.1 (M+).
[0147]Under the protection of nitrogen, 0.5 g (1 mmol) compound 3 was placed in a 25 ...
example 3
[0150]Preparation of (R)-4-(2-chloro-4-fluorophenyl)-6-methyl-2-(2-thiazolyl)-1, 4-dihydropyrimidin-5-trifluoroethylcarboxylate
[0151]
[0152]According to the method of Example 2, while using sodium trifluoroethoxide in place of sodium ethoxide, 0.296 g of a yellow amorphous solid compound 5 was obtained (yield 78%),
[0153]1H-NMR (400 MHz, DMSO-d6) δ 4.60-4.64 (2H, m); 6.01 (1H, s); 7.16-7.21 (1H, m); 7.34-7.43 (2H, m); 7.92-7.93 (1H, d); 7.98-7.99 (1H, d); 10.23 (1H, s); MS (EI)-432.1 (M+)
[0154][α]D=−80.1 (c=1%, CH3OH).
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